Immunological Reagents

Active Publication Date: 2017-06-15
MABQUEST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the long-term suppression of HIV replication achieved in patients with optimal adherence to ART, HIV invariably rebounds after interruption of therapy.
Furthermore, successful therapy does not induce or allow restoration/development of virus-specific immune respo

Method used

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  • Immunological Reagents
  • Immunological Reagents
  • Immunological Reagents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Generation and Characterization of PD-1 Binding Agents

[0108]Four mice strains (total of 16 mice) have been immunized with two PD-1 proteins, i.e. human PD-1 Fc fusion protein and a human PD-1 monomeric protein. Mice showing serum reactivity to PD-1 expressed on activated human T lymphocytes have been selected for generation of anti-PD-1 hybridoma cell lines. A total of 240 PD-1 hybridoma cell lines were selected for producing antibodies that bind to recombinant PD-1 protein. The primary criteria for the first round of antibodies selection were: i) staining of PD-1 on activated human T lymphocytes by flow cytometry; ii) diversity of CDR VH and VL sequences as compared to those of the existing anti-PD-1 antibodies; and, iii) epitope mapping performed by competitive binding studies with PD-1 conjugated Luminex beads with two commercially available anti-PD-1 antibodies binding to different epitopes on PD-1. A second round of selection was then carried out by: iv) affinity binding assays...

example 2

Antibody Combinations

[0111]Combinations of antibodies binding to different PD-1 epitopes were found to enhance restoration of HIV peptide specific CD8 T-cell proliferation in a functional exhaustion recovery assay (FIG. 8). Synergy between antibody types was also observed. For instance, it was determined that class 1 (MK-3475 in FIG. 8) and class 2 (139D6 in FIG. 8) antibodies are able to simultaneously bind PD-1. While the maximum stimulation observed for MK-3475 is consistently about 200% relative to the HIV peptide, combinations of MK-3475 and 139D6 monoclonal antibodies at 5 μg / ml exhibited synergy with a 288% increase in HIV-specific CD8 T cell proliferation relative to the HIV peptide control alone or a 144% increased proliferation relative to MK-3475 or 139D6 added alone (FIG. 8). This synergistic increase in proliferation was observed in several experimental tests with a statistically significant p value of 0.007. As a comparison, addition of 10 μg / ml of either MK-3475 or 13...

example 3

Epitope Mapping of Anti-PD-1 Antibodies

[0112]Preliminary epitope mapping evaluations relied on biochemical competitive binding assay studies between commercially available anti-PD-1 antibodies (EH12.2H3 and J116) and the newly identified anti-PD-1 antibodies defined in this patent. This procedure allowed us to categorize the antibodies into one of four binding classes based on binding competitively or non-competitively with either of the two commercial antibodies. A more precise method of defining the antibody binding epitopes on PD-1 is to monitor the interaction of the antibody with different PD-1 proteins that have discreet amino acid substitutions at solvent accessible residues. If these residues are important for tight binding of the anti-PD-1 antibodies, the substitution can result in a reduced binding for the PD-1 protein. These studies were performed by site directed mutagenesis of the PD-1 gene encoded within the pReceiver-M67 mammalian expression vector under the control o...

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Abstract

This disclosure relates to binding agents with specificity for programmed cell death 1 (PD-1) and to methods for using the same to treat, prevent and/or ameliorate an infectious disease (e.g., human immunodeficiency virus (HIV)), cancer and/or autoimmunity. In addition, this disclosure identifies a novel binding patch (“P2”) on PD-1 that is linked with a previously unidentified functional activity of PD-1 that is distinct from the interaction site involved with either the PD-L1 or PD-L2 ligands. Furthermore, we demonstrate that antibodies that interact with this region of PD-1 are able to act as antagonists of PD-1 and that this antagonism is further enhanced with the addition of antibodies that act through the blockade of the PD-1/PD-L1/L2 interaction.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 15 / 014,749, which is a continuation-in-part of PCT / IB2015 / 055943, with an international filing date of Aug. 5, 2015, which claims priority to U.S. Ser. No. 62 / 033,177 filed Aug. 5, 2014; U.S. Ser. No. 62 / 053,366 filed Sep. 22, 2014; and U.S. Ser. No. 62 / 093,368 filed Dec. 17, 2014. U.S. Ser. No. 15 / 014,749 also claims priority to U.S. Ser. No. 62 / 286,269 filed Jan. 22, 2016. Each of these applications are hereby incorporated into this disclosure in their entirety.FIELD OF THE DISCLOSURE[0002]This disclosure relates to binding agents with specificity for programmed cell death 1 (PD-1) (e.g., human PD-1) and to methods for using the same to treat and / or prevent infection (e.g., by human immunodeficiency virus (HIV)), cancer and / or autoimmunity.BACKGROUND OF THE DISCLOSURE[0003]As we enter the fourth decade of the HIV epidemic, significant advances have been made in the understanding of HIV pathogenesis and i...

Claims

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Application Information

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IPC IPC(8): C07K16/28
CPCC07K16/2818C07K2317/92C07K2317/76C07K2317/21C07K2317/24C07K2317/565C07K2317/33C07K2317/34A61K2039/507C07K2317/74C07K2317/75C07K16/1063C07K2317/31G01N33/6893
Inventor PANTALEO, GIUSEPPEFENWICK, CRAIG
Owner MABQUEST
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